An efficient mass treatment for cyanide poisoning due to accidental or intentional exposure is essential for public health. Cyanide poisoning is rapid and treatment options are limited, and thus the survival rate is low.
Cyanide is used industrially in tasks, such as fumigation, electroplating, and mining. It is well known in suicides, homicides, and warfare and is increasingly recognized as a toxin in building fires. It is formed in thermal combustion of nitrogen-containing polymers, which release carbon monoxide and cyanide faster than natural products such as wood (see Alarie, Y., Annu. Rev. Pharmacol. Toxicol. 25, 325-347 (1985)). Cyanide is therefore considered a common cause for inhalation injury in all uncontrolled building fires in the civilian population (see Anderson, R. A. and Harland, W. A., Med. Sci. Law 22, 35-40 (1982); and Ballantyne, B. In Clinical and Experimental Toxicology of Cyanides (B. Ballantyne and T. Marrs, Eds.), pp. 248-291 (1974); and in Clark, C. J., Campbell, D., and Reid, W. H., Lancet 1, 1332-1335. and same authors in Hum. Toxicol. 6, 139-145 (1981); and in Silverman, S. H., Purdue, G. F., Hunt, J. L., and Bost, R. O., J. Trauma 28, 171-176 (1988)).
Several international organizations, including the World Health Organization (WHO) have designated cyanide a priority chemical in relation to potential impact on human health and the environment.
Cyanide is naturally metabolized in the liver by cysteine 247 in the rhodanase enzyme active site. The rhodanase is activated by donation of sulfur from the sulfane pool to form cysteine perthiol, (—SSH), which reacts instantaneously with cyanide to form nontoxic thiocyanate. Natural substrates for cyanide metabolism become depleted rapidly when cyanide exposure is high. Cyanide is a specific inhibitor of cytochrome c oxidase, resulting in histotoxic hypoxia, followed by lactic acidosis as a consequence of anaerobic cell (see Steven J. Baskin, and Thomas G. Brewer, “Cyanide Poisoning,” “Medical Aspects of Chemical and Biological Warfare,” (Frederick R. Sidell, COL Ernest T. Takafuji, and COL David R. Franz, Eds.) and “Textbook of Military Medicine: Medical Aspects of Chemical and Biological Warfare”, (BG Russ Zajtchuk and COL Ronald F. Bellamy, Eds.), Office of the Surgeon General, Walter Reed Army Medical Center, Washington, D.C. (1997)).
A lethal blood concentration of cyanide has been found to depend on exposure level and amount of oxygen in the blood. For example, oxygen deprivation due to concurrent carbon monoxide inhalation at high levels increases the LT50 tenfold (see see Alarie, Y., Annu. Rev. Pharmacol. Toxicol. 25, 325-347 (1985)).
A lethal cyanide dose can be a large range: from 1.0 to 6.0 mg/L (40 to 200 μM). Half-life of cyanide at toxic levels, where blood tests were obtained in the ambulance shortly after exposure (see S. W. Borron, B. Mégarbane., F. J. Baud, Case 6-2004: Severe Burns from a Nightclub Fire. New England Journal of Medicine 2004, 2314.), has been determined as 1 hour, while studies showed that in nonfatal cases a half-life of 3 h was determined (see Barillo, D. J., J. Burn Care Rehabil., 15, 46-57 (1994); Kratz, A., Ferraro, M., Sluss, P., Lewandowski, K. B., Laboratory Reference Values. N. Engl. J. Med., 351, 1548-1563 (2004)). Lower-level inhalation exposure or oral ingestion has a survival time of about 30 min (see). Biological detoxification of cyanide from the human body takes place through a variety of minor pathways (see 1Keilin, D., Proc R Soc Lond [Biol] 106:418-444 (1930); Isom, G. E. and Way J. L., Toxicol. Appl. Pharmacol. 74:57-62 (1984)).
The rate of natural detoxification of cyanide by the rhodanese enzyme has been measured as 0.017 mg/kg*min (see McNamara, B. P., Estimation of the toxicity of hydrocyanid acid vapors in man. (Edgewood Arsenal Technical Report No. EB-TR-76023, Army Department (1976)). Because of the rapidly progressive nature of cyanide toxicity, treatment is ideally administered shortly after exposure. Antidotes and treatments are often administered with oxygen, or thiosulfate.
Conventional approaches for treating cyanide poisoning may be organized into the following groups:
Methemoglobin Inducers.
This group counts amyl and sodium nitrites, and DMAP or 4-dimethylaminophenol. Nitrites oxidize hemoglobin to methemoglobin, which has higher affinity for cyanide than for oxygen. Methemoglobin chelates cyanide to form cyanomethemoglobin at the cost of oxygen-carrying capacity and is known to cause hypotension (see Hall and Kulig 1989). Carboxyhemoglobin formed upon inhalation of carbon monoxide causes oxygen deprivation, and using methemoglobin formers to treat cyanide poisoning concurrently has been shown to increase victim fatality (see Moore, S. J., Norris, J. C., Walsh, D. A., Hume, A. S., The Journal of Pharmacology and Experimental Therapeutics, 242(1), 70-74, (1987)). DMAP or 4-dimethylaminophenol is used only for severe cyanide poisoning because it involves significantly increased risk of oxygen deprivation or anoxia (see Baskin and Brewer), and unsuitable for treatment of fire victims. Nitrites in combination with thiosulfate have been the most used treatments in USA.
Chelators.
This group counts vitamin B12 derivatives, and EDTA. Hydroxocobalamin (vitamin B12) is a cyanide chelator without significant side effects. Hydroxocobalamin was approved for use in Cyanokit™ (Merck Sante s.a.s.) by Food and Drug Administration (FDA) in USA in December 2006. The doses required for treatment are in the range of 5 to 20 g per patient. Adverse event reports include skin discoloration from pink to red and red-colored urine, which resolves over a few days (see S. W. Borron, F. J. Baud, B. Mégarbane, C. Bismuth, Am. J. Emer. Med., 25, 551-558, (2007)). The compound is nontoxic and has been used widely in Europe. The drawbacks include a short shelf life and light sensitivity, and a costly dose. It is unsuitable for mass treatment. Dicobalt edetate (cobalt EDTA or Kelocyanor) is more effective than the combination of sodium nitrite and sodium thiosulfate, but severe toxicity of cobalt in the absence of cyanide is a deterrent to using treatments like cobalt EDTA without solid proof of cyanide intoxication. Cobinamide has progressed towards clinical trials (see Brenner, M., Kim, J. G., Lee, J., Mahon, S. B., Lemor, D., Ahdout, R., Boss, G. R., Blackledge, W., Jann, L., Nagasawa, H. T., Toxicol Appl Pharmacol, 248:269-276 (2010)). It is a highly soluble vitamin B12 precursor and has higher efficacy than Cyanokit™. It reacts stoichiometrically with cyanide.
Other Treatments.
This group counts thiosulfate, and a mercaptopyruvate prodrug. Thiosulfate has been used off-label for a long time. It is now in the process of FDA approval. It reacts with cyanide as it is slowly released from cyanomethemoglobin, forming thiocyanate. Thiosulfate treatment requires intravenous administration of large quantities (see Ivankovich, A. D., Braverman, B., Kanuru, R. P., Heyman, H. J., and Paulissian, R., Anesthesiology, 52, 210-216 (1980) or ˜12 g/10 min as is the current standard. Additionally, thiosulfate is commonly administered with other treatments to facilitate thiocyanate formation since it does not affect oxygen carrying capacity in fire victims. The reaction rate of thiosulfate with cyanide is too slow to save lives by itself. Mercaptopyruvate prodrug or sulfanegen, is recent development and appears safe, and moderately effective. It is administered intravenously, where β-mercapto-pyruvate sulfur-transferase transforms it into the active drug. The downside is that it is rather unstable (Brenner, M., Kim, J. G., Mahon, S. B., Lee, J., Kreuter, K. A., Blackledge, W., Mukai, D., Patterson, S., Mohammad, O., Sharma, V. S., Boss, G., Ann. Emerg. Med., 55:32-362 (2009)).
The treatments known in the art as described above have in common either a requirement for a large quantity of treatment, risk of toxicity, or a requirement for IV administration.
Accordingly, there is a need for a new cyanide poisoning treatment that requires only a small dose of nontoxic compounds suitable for treatment of several victims suffering from smoke inhalation or industrial accidents.